1. Field of the Invention
The present invention provides a prophylactic or therapeutic agent for allergic ophthalmic diseases or allergic nasal diseases, comprising a tricyclic triazolobenzazepine derivative. More particularly, the present invention provides a pharmaceutical composition for use in the prophylaxis or treatment of allergic ophthalmic diseases or allergic nasal diseases, comprising 7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo[4,5-c][1]benzazepine, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
2. Background Art
Allergic ophthalmic diseases are symptoms related to eyes and their peripheral tissues based on an allergic reaction induced by various stimulations such as an immunoreaction. Specific examples thereof include seasonal allergic conjunctivitis, chronic allergic conjunctivitis, vernal conjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis. Among them, the pathologic condition of the allergic conjunctivitis is mainly an inflammatory disease of conjunctiva/cornea based on type I allergic reaction. The type I allergic reaction is biphasic reaction comprising early phase (immediate-type reaction) and late phase (delay-type reaction).
The early phase appears 15 to 30 min after the exposure of antigen and disappears 1 to 2 hr after that. The late phase appears 6 to 12 hr after the disappearance of the early phase and continues for 24 to 48 hr (see Hansen I. et al.: Mediators of inflammation in the early and the late phase of allergic rhinitis. Curr. Opin. Allergy Clin. Immunol. 4; 159-163, 2004). In the early phase, symptoms such as itching, dacryorrhea, hyperemia, and conjunctiva and palpebral edema appear through the action of chemical transmitters such as histamine released from mast cells. On the other hand, the late phase is a persistent inflammation reaction induced by the invasion of inflammatory cells such as T cells and eosinophils, cytokines/chemokines produced therefrom, and toxic proteins released from the eosinophils. The late phase is considered to participate in increased severity and procrastination of the pathologic condition (see Azuma Kozue, Ohno Shigeaki: Arerugisei Ketsumaku Shikkan Gaisetsu (Outline of allergic conjunctival diseases) “NEW MOOK Ganka (Opthalmology); Arerugisei Gan Shikkan (Allergic ophthalmic diseases) 6,” edited by Ohno Shigeaki et al., KANEHARA & Co., LTD., 1-5, 2003).
For the early phase, cromoglycate, an inhibitor of histamine release, and antihistamines are effective (see King H. C.: Pharmacotherapy of allergic rhinitis. in “Allergy in ENT Practice The basic guide 2nd” ed. by King H. C. et al. Thieme Medical Publisher, Inc. 178-204, 2005). On the other hand, the late phase is induced, for example, by cytokines/chemokines and toxic proteins in addition to histamine (see Kramer M. F. et al.: Nasal IL-16 and MIP-1α in late-phase allergic response. Allergy and Asthma Proc. 22; 127-132, 2001; Economides A and Kaliner M. A.: Chapter 5 Allergic rhinitis. in “Current Review of Rhinitis” ed by Kaliner M. A. Current Medicine, Inc. 35-51, 2002). These play a main role in the inflammation in the late phase. In this connection, there is a report that even levocabastine, which is the most potent antihistamine agent, cannot inhibit the late phase (see Hingorani M. and Lightman S.: Ocular Allergy in “Allergy and Allergic Diseases” ed by A. B. Kay Blackwell Science, Inc. 1645-1670, 1997).
Steroids have a potent cytokine/chemokines production inhibitory activity and a very potent effect against the late phase (see Ciprandi G. B et al.: Defrazacort protects against late-phase but early-phase reactions induced by the allergen-specific conjunctival provocation test. Allergy 48; 421-430, 1993). The steroids, however, has a risk of side effects such as cause increased ocular pressure and onset of glaucoma. Accordingly, short-term use thereof is recommended. Further, a check on the side effect by ocular specialist physicians should also be periodically carried out (see Takamura Etsuko: Arerugisei Ketsumaku Shikkan No Meno Kayumi No Seiin To Chiryo (Cause and treatment of ocular itching in allergic conjunctivitis. Allergology 19; 444-449, 2005; Barney N. P. and Graziano F. M.: Allergic and immunological diseases of eye, in Middleton's Allergy principles & practice 6th edition ed. by Adkinson N. F. et al. Mosby, Inc. 1599-1617, 2003). Accordingly, there are many restrictions in the use of steroids in allergic ophthalmic diseases, and, thus, the use of the steroids is troublesome.
Thus, the development of pharmaceutical preparations for treating and preventing allergic ophthalmic diseases, which is also effective in late phase and has no side effect, has been still desired.
Allergic nasal diseases are symptoms related to nose and its surrounding tissues based on an allergic reaction caused by various stimulations such as an immunoreaction. Specific examples thereof include seasonal allergic rhinitis, perennial allergic rhinitis, and allergic sinusitis. The clinical condition of the allergic rhinitis is also based on a type-I allergic reaction.
In the early phase of the type-I allergic reaction, for example, sneezing, itching, rhinorrhea, and edema of nasal mucosa appear due to chemical mediators such as histamine released from mast cells. Also in the early phase, as in the case of ophthalmic diseases, cromoglycate, an inhibitor of histamine release, and antihistamines are effective. In the late phase, however, in addition to histamine, cytokines/chemokines and toxic proteins produced by infiltrated inflammatory cells, such as T cells and eosinophils, induce the above symptoms. Accordingly, it is reported that any satisfactory effect cannot be attained by merely blocking the action of histamine (see Bensch G. W. et al.: Evaluation of cytokines in nasal secretions after nasal antigen challenge: lack of influence of antihistamines. Ann. Allergy Asthma immunol. 88; 457-462, 2002). The late phase is considered to participate in increased severity and procrastination of the pathologic condition, and, in fact, internal medicines of antihistamine agents are widely used as basic prescribed medicines for rhinitis. It is reported that additional administration of a nasal drop of an antihistamine agent to a patient suffering from rhinitis, however, does not improve the effect (see Bereger W. E. et al.: Efficacy of azelastine nasal spray in patients with an unsatisfactory response to loratadine. Ann. Allergy Asthma Immunol. 91; 205-211, 2003; LaForce C. F. et al.: Efficacy of azelastine nasal spray in seasonal allergic rhinitis patients who remain symptomatic after treatment with fexofenadine. Ann. Allergy Asthma Immunol. 93; 154-159, 2004). This supports the fact that the symptom induced by inflammatory cells invaded in the late phase cannot be suppressed by the antihistamine agent without difficulties.
Steroids have a potent cytokine/chemokine production inhibitory activity and exhibit a highly potent effect against the late phase in an allergic reaction of an allergic rhinitis (see Drain K. L. and Li J. T. C.: chapter 17 Corticosteroids and their use in rhinitis. in “Current Review of Rhinitis” ed. by Kaliner M. A. Current Medicine, Inc. 163-173, 2002). Regarding the clinical effect in the rhinitis as well, steroids have been confirmed to surpass antihistamine agents (see Schleimer R. P. et al.: glucocorticoids in “Middleton's Allergy Principles & Practice Sixth edition” ed by Adkinson Jr. N. F. et al Mosby, Inc. 870-913, 2003). The steroids, however, sometimes induce local side effects in noses such as nasal bleeding, local stimulation, and drying (see the above-described Drain K. L. and Li J. T. C.: chapter 17 Corticosteroids and their use in rhinitis. in “Current Review of Rhinitis” ed by Kaliner M. A. Current Medicine, Inc. 163-173, 2002). In patients who suffers from an allergic disease complicated by other allergic diseases such as asthma and atopic eczema and already use steroids, in some cases, the addition of a nasal steroid sometimes causes excessive exposure to the steroid and increases a risk of the systemic side effect (inhibition in hypothalamus-hypophysis-adrenal system and inhibition of the growth in early adolescence). For these reasons, there are many restrictions in the use of steroids in allergic nasal diseases.
Accordingly, the development of pharmaceutical preparations for treating and preventing allergic nasal diseases, which are also effective in the late phase, is less likely to cause side effect and, have still been desired in the art.
7,8-Dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo[4,5-c][1]benzazepine (hereinafter referred to as “compound A”) is a compound having the following structure and is known to have antiallergic activity (see WO 95/18130 (Japanese Patent No. 3290664 and U.S. Pat. No. 5,686,442).

This document (the above-described WO 95/18130), however, relates to effective ingredients in oral preparations (tablets and capsules) for preventing allergic diseases. In fact, pharmacological test examples show only the prophylactic effect on the inhibition of an allergic reaction by the oral administration of tricyclic benzazepine derivatives containing compound A. Specifically, the document discloses the prophylactic effect on the inhibition of an allergic reaction in the skin of the foot by orally administering a tricyclic benzazepine derivative before the onset of the allergic reaction. Further, the document describes that the onset inhibitory effect (inhibition ratio) is about 50%.
As described above, cromoglycate, which inhibits the release of histamine, is effective in the early phase of the allergic reaction. The following fact, however, should be noted. The cromoglycate, when administered before exposure to an antigen, is effective, but on the other hand, after the induction of the allergic reaction, the effect disappears. Accordingly, the cromoglycate has been regarded as having such a property that the onset of action is slow and the action is moderate. On the other hand, the clinical judgment is such that, since the treatment is started in a symptomatic state, a satisfactory clinical effect cannot be expected by mere prophylactic effect without difficulties. Thus, the development of therapeutic effect, upon the administration of a medicament after the onset of the allergic reaction, is very important.
2-(1-Isopropoxycarbonyloxy-2-methylpropyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine (hereinafter often referred to as “compound B”) is a prodrug of compound A and has the following structure. It is known that compound B, after passage through mucous membranes of digestive tracts, is converted to compound A in vivo and develops antiallergic action as its drug efficacy. It has been demonstrated that compound B, as compared with compound A, can improve the absorption upon oral administration by a factor of seven (see WO 99/16770 (Japanese Patent No. 3188482 and U.S. Pat. No. 6,372,735).

This document (the above-described WO 99/16770), however, also relates to active ingredients of oral preparations for preventing allergic diseases, and only oral preparations such as tablets and fine subtilaes are disclosed as formulation examples. Further, pharmacological test examples disclosed in the document also relate to oral preparations.
In general, it cannot be necessarily said that, even when an active ingredient is absorbed into the living body through mucous membranes, for example, in digestive tracts and exhibits an excellent effect, an excellent effect favorably comparable with the oral administration can be attained in parenteral administration. For example, when a parenteral preparation is topically administered to mucous membranes in target organs of allergic diseases, the contemplated active ingredient acts directly on the affected part. Accordingly, a lot of consideration should be placed on the dose and dosage form. Further, the possibility of side effects caused by direct action is also not negligible. In general, these matters should be studied separately from the finding in the oral administration.